The role of Toxoplasma gondii in multiple sclerosis: A matched case-control study
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Neurology Asia 2021; 26(2) : 333 – 339
The role of Toxoplasma gondii in multiple sclerosis:
A matched case-control study
1
Masoud Keighobadi, 2Nafise Danesh Alokandeh, 3Seyed Mohammad Baghbanian,
4
Narges Karimi
1
Toxoplasmosis research center, Mazandaran University of Medical Sciences, Sari; Iran;2Mazandaran
University of Medical Sciences, Sari, Iran; 3Department of Neurology, Faculty of Medicine, Mazandaran
University of Medical Sciences, Sari, Iran; 4Department of Neurology, Toxoplasmosis research center,
Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
Abstract
Background & Objectives: Toxoplasma (T.) gondii is an intracellular parasite that has recently been
reported in association with multiple sclerosis (MS) and other autoimmune diseases, with an unidentified
function. The aim of this project was to investigate the seroprevalence of T. gondii in MS patients
in comparison with healthy people. Method: This case-control prospective study was conducted on
90 patients with MS and 90 age and gender-matched healthy participants. All patients and healthy
individuals filled a sociodemographic questionnaire and MS patients were evaluated for clinical
status. The presence of specific IgG and IgM antibodies against T. gondii was explored by using an
enzyme immunoassay test in the sera of the participants. Results: The mean age of MS patients was
34.47±8.74. Out of 90 MS patients, 70 (77.8%) were female. No significant difference was observed
between both groups with respect to age and gender. Anti-T. gondii IgG antibodies were found in 47
(52.2%) of the 90 cases and in 79 (87.8%) of the 90 controls (P = 0.0001). Mean age and disease
duration of the seropositive MS patients were 36.76±7.78 and 5.12±3.64 years, respectively. There
was significant association between T. gondii seropositivity and age and also disease duration (P=0.009
and 0.033, respectively).
Conclusion: The results of this study showed that the seroprevalence of T. gondii in MS patients
is lower than the healthy group. These results suggest that there is a negative association between
infection with T. gondii and MS and toxoplasmosis can be considered as a possible protective factor
for the development of MS.
Keywords: Toxoplasmosis, multiple sclerosis, prevalence, IgG antibody, IgM antibody
INTRODUCTION research has established that parasitic infections
may be accompanied with a lower possibility
Multiple Sclerosis (MS) is a chronic, inflammatory,
of MS.7-8 Also, some earlier studies evaluated
and demyelinating multifocal disease that affects
the association between toxoplasmosis and MS
the central nervous system (CNS).1-2 The etiology
and found contradictory findings.9-12 Toxoplasma
of MS, similar to other autoimmune diseases,
Gondii (T. gondii) is an intracellular parasite that
is still unclear; but the combination of genetic
can cause a lifelong chronic infection in the host.13
proneness and environmental influences can lead
The prevalence of T. gondii infection in humans
to creating of the development of this disease.3-4
worldwide, based on IgG measured against T.
One of the most prominent environmental factors
gondii, has been reported to be around 6 billion.13
in MS pathogenesis is infectious agents such
Daryani et al. showed that the general prevalence
as human herpesvirus 6 (HHV-6), Epstein-Barr
of T. gondii infection in the Iranian population
virus (EBV), and Chlamydia pneumoniae. 5
is approximately 40%.14 Moreover, data from
Recently, there has been growing interest in
several studies suggest that chronic T. gondii
the correlation between parasitic infections and
infection may have a role in some disorders, such
autoimmune disorders such as MS. This issue
as cognitive impairment, cryptogenic epilepsy,
has been studied widely since 1989.6 Previous
Address correspondence to: Narges Karimi, Department of Neurology, Pasdaran Boulevard, Bou Ali Sina Hospital, Sari city, Mazandaran province,
4815838477 Iran. Tel: +981133343018; Mobile: +989122029074; Email: Drkarimi_236@yahoo.com
Date of Submission: 4 December 2020; Date of Acceptance: 22 January 2021
333Neurology Asia June 2021
headache, and neurodegenerative disorders, consuming anti-parasitic drugs, having immune
which may be due to direct parasite attack or deficiencies (leukemia, lymphoma, malignancy,
immunological damage affected by the parasite and AIDS) and other neurological disorders such
or both.15-18 There is evidence that interferon- as Parkinson’s disease, Alzheimer’s disease,
gamma (IFNγ), produced by microglial cells, epilepsy, and diabetes mellitus.
plays a crucial role in immunological protection This study was approved by the Institutional
against toxoplasmosis.19 However, IFNγ may Research Ethics Review Board of Mazandaran
result in the production of nitric oxide (NO) University of Medical Sciences (IR. MAZUMS.
that is a key element of tissue damage.19-20 On REC.1398.3570). The study has been extracted
the other hand, Rozenfeld et al. reported that from a medical student thesis with the project
activated microglia produce interleukin-10 (IL- number, 3570.
10) and indirectly induce astrocyte activity and All patients and healthy individuals filled a
also prostaglandin E2 (PGE2) production.21 It sociodemographic questionnaire, which included
has been conclusively shown that PGE2 may such information as age, gender, place of
play a neuroprotective role, as a result of the residence, educational level, occupation, marriage
extinguishing Th1 pro-inflammatory cytokine, the status, and cat keeping or touching. In addition,
inducing Th2 cytokines like the interleukin- 10, other information was obtained from the patients
and the decreasing NO production via activated regarding disease duration, annualized relapse
microglia.22 This mechanism is indicated as rates, extended disability status scale (EDSS),
an indirect protective effect of neurons by pattern of MS, and type of medication consuming.
toxoplasmosis.21 The main challenge faced by Venous blood samples (5 ml) were achieved
many researchers is disagreement on the role from all participants for serological tests. Sampling
of T. gondii in MS. While several researchers was done in MS clinic and testing was carried out
identified T. gondii as a protective factor, others at the university Clinic Laboratory (Bagheban).
reported it as a risk factor.10-12,23 A meta-analysis All blood samples were stored at −20°C and
study demonstrated a lower prevalence of T. analyzed for anti-toxoplasma IgG and IgM
gondii in MS patients compared to control antibodies using enzyme-linked immunosorbent
group, but no significant relationship was found assay (ELISA) (ELISA Kit, Toxo IgG & IgM,
between toxoplasmosis and MS.24 Thus, the actual Pishtazteb, Iran). The sensitivity of both IgG and
relationship between toxoplasmosis and MS IgM kits was 100%, and the specificity of IgG
remained uncertain. Therefore, the aim of this and IgM kits was 100 and 99%, respectively.
study was to evaluate the role of T. gondii in MS. Repeated freezing and defrosting were avoided
for all samples. We used automatic ELISA reader
METHODS with capacity of optical density at 450 nm, and
the results were interpreted according to the
This case-control prospective study was conducted
related guidelines. The IgM values at 0.90 IU/
on 90 patients with clinically definite diagnosis
mL were interpreted as negative, those at 0.91
of MS and clinically isolated syndrome (CIS)
to 1.09 IU/mL as borderline, and those at 1.10
according to McDonald’s criteria for diagnosing
and above as positive. The IgG values at 8 IU/
MS.25 All patients were randomly selected, then
mL were considered as negative, 11 IU/mL and
assessed and followed up in the outpatient clinic
above as positive, and between 8.1-11 IU/mL as
of MS at Bou-Ali Sina Hospital, Mazandaran
suspicious.
province, Iran over one year from December 2017
to January 2019. Meanwhile, the control group
Sample size and statistical analysis
included a total of 90 healthy volunteers matched
with cases for age and gender; all individuals were For the sample size calculation, we used the
randomly selected from the population referring following values: a 95% confidence level, a
to the clinic. power of 80%, a 1:1 proportion of cases and
The inclusion criteria were definite diagnosis controls, and a reference seroprevalence of
of MS and CIS based on McDonald’s criteria, 55%25 as the expected frequency of exposure in
aged 18 years and older, and the patients in the controls and 33.9% in intervention group. Thus,
remission period who accepted to participate in a total of 90 cases and 90 controls were randomly
the study. selected. Statistical analysis was performed using
The exclusion criteria were receiving SPSS software version 24 (SPSS Inc., Chicago,
intravenous corticosteroids in the past 3 months, Illinois, USA). Continuous data were stated as
334mean±standard deviation (SD), whereas frequency between the two groups (P=0.45). The results of
data were presented as percentages (%). The sociodemographic characteristics in two groups
Chi-square and Student’s t-test were used to test are illustrated in Table 1. The mean of EDSS score
statistically significant differences for parametric and mean disease duration was 2.62 ±1.91 (range:
data. P-values less than 0.05 were considered 1-7.5) and 6.05±4.29 (range: 0.50-20) years,
statistically significant. respectively. Also, the annualized relapse rate
(ARR) was 0.62±0.91 (range: 0-4). Regarding the
RESULTS patterns of disease progression, 66 (73.33%), 16
(17.77%), 10 (11.11%), and 4 (4.44%) of patients
A total of 180 subjects (90 MS patients and 90
were relapsing-remitting (R-R), CIS, secondary
healthy controls) participated in this study. The
progressive (S-P), and primary progressive (P-P),
mean age of MS patients and healthy controls
respectively. All MS patients received disease-
was 34.47±8.74 and 34.25±8.11, respectively.
modifying therapies (DMTs) who, 34 (37.8%)
Out of 90 MS patients, 70 (77.8%) were female.
patients administrated interferon-beta and 27
No significant difference was observed between
(30%) received rituximab. The remaining patients
the two groups with respect to age and gender
29 (32.2%) obtained oral DMTs.
(P=0.86 and P=0.71, respectively). Regarding
the place of residence, 68 patients (75.6%) and
Seroprevalence and titer of anti-T. gondii IgM
73 healthy people (81.1%) lived in urban areas,
and IgG
and no significant difference between the two
groups was reported (P=0.47). In terms of being The results obtained for anti-T. gondii IgG titer
in contact with cats, none of the participants were among 0 to 276 IU/mL with the mean value
kept a cat in the house but 36 patients (40%) of 67.51±86.21 IU/mL in the case group, and 0 to
and 42 controls (46.7%) stated that they had 260 IU/mL with the mean of 97.74±72.59 in the
touched cats. No significant difference was found control group. There was a significant differences
Table 1: Demographic data and serologic characteristics of participants
Variables MS patients Healthy group * p-value
Age; Mean± SD 34.47±8.74 34.25± 8.11 0.86
Gender; n (%)
Male 20(22.2) 17(19.9)
Female 70(77.8) 73(81.1) 0.71
Educational level; n (%)
Illiterate 4(4.4) 6(6.7)
Primary school 6 (6.7) 1(1.1)
Under diploma 30 (33.3) 32(35.6)
Diploma 11(12.2) 10(11.1)
University education 39(43.3) 41(45.5) 0.51
Place of residency; n (%)
Urban 68(75.6) 73(81.1)
Rural 22 (24.4) 17(18.9) 0.47
Occupation; n (%)
Housewife 51(56.7) 58(64.4)
Employed 14(15.6) 17(18.9)
Unemployed 25(27.8) 15(16.7) 0.19
Touched cat; n (%)
Yes 36(40) 42(46.7)
No 54(60) 48(53.3) 0.45
a
Seropositivity IgM; n (%) 1(1.1) 1(1.1) 0.75
a
Seropositivity for IgG; n (%) 47(52.2) 79(87.8) 0.0001
IgG titer; Mean ±SD 67.51±86.21 97.74±72.59 0.012
IgM titer; Mean ±SD 0.15±0.63 0.18±0.74 0.76
* p-valueNeurology Asia June 2021
between the two groups (t (178)= -2.54, P=0.012). patients were statistically significant (P=0.80
All participants were negative for anti-T. gondii and P=0.20, respectively). The mean of EDSS
IgM with the exception of one participant in in seropositive and seronegative MS patients
both case and control groups, who had anti-T. was 2.61±1.95 and 2.62±1.89, respectively.
gondii IgM titer above 1.1 IU/mL (6.1 and 7.1 Also, there was no significant difference between
IU/mL, respectively). T-tests found no significant EDSS and anti-T. gondii IgG (P=0.99). But there
differences in mean scores of anti-T. gondii IgM was a significant difference between anti-T.
titer between the two groups (P=0.76). Overall, gondii IgG seropositivity and mean disease
47 patients (52.2%) and 79 controls (87.8%) had duration, so that seropositive MS patients had a
anti-T. gondii IgG titer of 11 IU/mL and above. shorter disease duration (t(88)=-2.19; P=0.033).
Also, there was a significant difference between Table 2 demonstrates the correlation between
the two groups (OR: 0.15; 95% CI: 0.72–0.32; anti-T. gondii IgG and characteristics of MS
P=0.0001, Chi-square test). Table 1 presents the patients. Out of 47 seropositive MS patients,
obtained results of the serological data of the two 34 (72.3%) were R-R, 7 (14.9%) CIS, 2 (4.3%)
groups. In terms of positive and negative T. gondii P-P, and 4 (8.5%) S-P. There was no significant
IgG with sociodemographic data in both groups, difference between seropositivity and type of
overall, no significant association was observed. disease (P=0.67). Regarding the patients receiving
DMTs, out of 34 (44.1%) patients receiving
The relationship of and anti-T. gondii IgG with interferon-beta, 15 were seropositive; and out of
demographic data among MS patients 27 patients receiving Rituximab, 18(67.7%) were
seropositive. There was no significant difference
The mean score for age was 36.76± 7.78 and
between seropositivity and kind of DMTs received
31.97± 9.13 in anti-T. gondii IgG seropositive
(P=0.37). Figure 1 presents the frequency of
and seronegative MS patients, respectively.
seropositive and seronegative anti-T. gondii IgG
There was a significant differences between the
based on type of MS and DMTs received.
two groups (t(88)=2.68, P=0.009). Out of 47
seropositive MS patients, 32 (68.1%) were female
DISCUSSION
and 15 were male (31.9%). Also, there was a
significant difference between seropositive and The role of T. gondii infection in MS is still
seronegative MS patients with gender (OR:3.56; not completely clear. Currently, there are few
95%CI:1.16-10.87; P=0.021). The relative risk of studies about this association. Meanwhile, several
seropositivity in men was 2.7 times higher than studies have described contradictory outcomes.
that of women. In addition, out of 47 seropositive Accordingly, this study set out with the aim of
MS patients, 12 (25.5%) lived in the rural areas assessing the frequency and serum levels of
and 22 (46.8%) had a history of touching cats. toxoplasma antibodies (IgG and IgM) in MS
None of these differences, with regard to either patients compared to healthy population. Our
residence place or contact with cats, in the two findings indicated lower seroprevalence of T.
groups of seropositive and seronegative MS gondii infection and lower antibody titers of anti-T.
Table 2: The association between characteristics of MS patients with anti- T. gondii IgG.
Variables IgG positive (N=47) IgG negative (N=43) * p- value
Age; mean±SD 36.76±7.78 31.97±9.13 0.009
Gender; n (M/F) 15/32 5/38 0.021
Touch the cat; n (yes/ no) 22/25 14/29 0.20
Residency; n(urban/rural) 35/12 33/10 0.80
Disease duration; mean±SD 5.12±3.64 7.06 ±4.73 0.031
EDSS score; mean±SD 2.61±1.95 2.62±1.89 0.97
ARR; mean±SD 0.63±0.89 0.60±0.96 0.86
* p-valueFigure 1: frequency seropositive and seronegative anti-T. gondii IgG in according to type of MS and type of DMTs.
R-R=relapse-remitting; S-P=secondary-progressive; P-P=primary-progressive; CIS=clinical isolated
syndrome.
gondii IgG in MS patients than age- and gender- kappa B (NF-jB) through inducing of TGF-β
matched healthy controls. Therefore, these results functions.20-21,28 Contrary to this study, other
may support hygiene hypothesis. According studies demonstrated a higher seroprevalence
to the ‘hygiene hypothesis’, the diminishing of T. gondii antibody in MS patients than in
incidence of infections in early childhood can healthy controls; and therefore these studies
play an important role in the development of suggested that T. gondii is a possible risk factor
both autoimmune and allergic diseases due to for MS development.10,12 But a study conducted in
inappropriate response of the immune system and Kurdistan, Iran rejected any association between
the dysregulation of Th1 and Th2 cell activity.26 T. gondii infection and MS.29 Furthermore, a
In line with the present study, some previous meta-analysis of five studies about the role of T.
studies demonstrated a negative association gondii in MS revealed a lower seroprevalence of T.
between infection with T. gondii and MS.9,11 gondii in the MS patients compared to the healthy
Koskderelioglua et al. conducted a study in Izmir, group; but no significant correlation was found
Turkey and reported a low T. gondii seropositivity between toxoplasmosis and MS.24 It is unclear
(33.9%) in MS patients in contrast to the control why there were dissimilarities and controversy in
group (55%); also, Stascheit et al. found low levels the relationship between MS and seroprevalence
of antibodies against T. gondii in MS patients in of toxoplasmosis in the mentioned studies. This
Berlin, Germany.9,11 In a recent study, Nicoletti is presumably due to the discrepancy in study
et al. reported a low level of anti-T. gondii population and prevalence of toxoplasmosis in
antibodies in MS patients (29.5%) compared to the general papulation in certain regions. In the
healthy participants (45.4%).27 Accordingly, the current study, there was no significant relationship
low prevalence of toxoplasmosis in MS patients between the residence place and contact with cats
may represent a protective effect of this infection with the presence of anti-T. gondii. The findings
on MS. As mentioned in the literature review, the of this study are similar to those of the study
neuroprotective property of toxoplasmosis can by Koskderelioglua et al. and contrary to the
be related to the indirect effect of infection on results of Stascheit et al.9,11 In our study, similar
the microglia and astrocytes and the secretion of to some previous studies, almost two thirds of
transforming growth factor beta (TGF-β), PGE2, the participants lived in urban areas. Hence, it
and IL10. Beside, other protective factors may could be hypothesized that the prevalence of
include the reducing of IL-2 due to the activation toxoplasmosis depends on individuals’ lifestyle
of the forkhead box P3 (FoxP3) T cells as an and hygiene habits rather than place of residence.
immune-suppressive element, and suppressing of In this study, we investigated the relationship
the inflammatory molecules including inducible between seroprevalence of toxoplasmosis and MS.
actin filament (F-actin) depolymerization, nitric Our findings showed that there was a significant
oxide synthase (iNOS) and nuclear factor- difference in age and gender between seropositive
337Neurology Asia June 2021
and seronegative MS patients. Older age and male DISCLOSURE
gender had higher seropositivity rates among MS
Financial support: This work was partially
patients. However, previous studies found no
supported by a grant from the Mazandaran
significant difference between age and gender with
University of Medical Sciences, Sari, Iran.
serological status of MS patients.9,11 One study in
Germany reported that older age and male gender
Conflict of interest: None
are independent risk factors for seropositivity of
toxoplasmosis.30 In terms of disease duration, we
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